Transcript Azoles and Barbiturates

MEDICINAL CHEMISTRY OF
AZOLE & BARBITURATES
1
AZOLE: An azole is a class of five-membered nitrogen heterocyclic
ring compounds containing at least one other non-carbon atom of
either nitrogen, sulphur or oxygen.
• A majority of compounds produced by nature have heterocyclic rings
as part of their structures. Many heterocyclic rings are found as key
components in biological systems.
2
Classification:
• 1 nitrogen (and no other heteroatom)
Pyrrole:
N
• 2 or more nitrogen atoms
H
Pyrrole
Pyrazole
1
Imidazole
5
NH
N
N
Triazole
N2
N
4
N
N
H
3
Tetrazole
Triazole
Tetrazole
• 1 nitrogen atom and 1 oxygen atom
Oxazole
Isoxazole
• 1 nitrogen atom and 1 sulphur atom
Thiazole
Isothiazole
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Classification according to pharmacological actions
Adrenergic agents: Clonidine, Phentolamine, Tolazoline,
Cholinergic agents: Pilocarpine HCl
Sulphonamides: Sulphamethizole, Sulfisoxazole, Sulphamethoxazole.
Cephalosporins: Cefazoline sodium, Cefonacid sodium,
Ceforanide, Cefoperazone, Cefmetazole,
Cefotetan sodium, Cefixime, Cefotaxime sodium,
Diuretics: Muzolimine, Acetazolamide, Methazolamide
Cardiovascular agents: Saralasin, Methimazole
Antihistaminic agents: Famotidine, Cimetidine,
Analgesics: Etonitazene
Anti- inflammatory analgesics: Tolmetin, Phenylbutazone
Steroids: Imazodan, pimobendan
Amino acids: Histidine, tryptophan
Antiviral : Ribavirin, Ritonavir, Vidarabin, Acyclovir, Valacyclovir,
Ganacyclovir, Famciclovir, Penciclovir
Antineoplastic agents: Dacarbazine, Mercaptopurine
Immunotherapy: Levamisole
CNS depressants: Etomidate, Alprazolam, Midazolam, Triazolam
Antipsychotics: Ondansetron
CNS stimulants: Pentylene tetrazole, Methyl xanthines, Pemoline,
Isocarboxazid , Mazindol, Trazodone HCl
Vitamins: vitamin B1 , vitamin B12 .
IMIDAZOLE :
1
2
HN
N3
5
4
Imidazole is an azapyrrole. First prepared in 1858. Imidazole is a 5membered heterocyclic ring containing 2 nitrogen atoms at 1,3 positions.
e.g. Metronidazole, Benznidazole, Dacarbazine, Etomidate, Midazolam,
Flumenizil, Ondansetron, Pilocarpine hydrochloride, Saralasin,
Methimazole, Cimetidine, Imazodan, Histidine, Histamine, Burimamide,
Metiamide, Immepip, Thioperamide, Clobenpropit, 4-Methyl histamine,
Carnosine, Priscol, Privine, Azamicin, Butoconazole, Clotrimazole,
Econazole, Sulconazole, Oxiconazole, Ketoconazole, Miconazole,
Tioconazole, Allantion etc…
Imidazoline : Clonidine, Phentolamine, Tolazoline, Mazindol, Antazoline
phosphate, Naphazoline, Oxymetazoline, Xylometazoline.
Imidazolidine dione: Phenytoin, Ethotoin, Nitrofurantoin, Dantrolene
sodium
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Dacarbazine
Anticancer drug
cimetidine
antiulcer agent
Etomidate
CNS depressant
Ondansetron
antipsychotic
Azamycin
Antihistaminic
phenytoin
anticonvulsant
histidine amino acid
pilocarpine
cholinergic
Antihypertensive
Midazolam
CNS depressant
Muzolimine
diuretic
FUSED RING SYSTEMS INVOLVING IMIDAZOLE:
BENZIMIDAZOLES:
Thiabendazole
Antihelmentic
lansoprazole
Antiulcer drug
Albendazole
Anthelmentic
omeprazole
antiulcer drug
Etonitazene (analgesic)
Purine:
SH
H
N
N
N
N
Famciclovir (antiviral)
acyclovir
Mercaptopurine
anticancer drug
Azathiopurine (anticancer agent)
Methyl xanthines
Adenosine
NAD
Metronidazole USP:
N
N
O2N
CH3
CH2CH2OH
MOA: It enters the bacteria via electron transport protein ferredoxin, it is
reduced and then bind to DNA causing loss of helical structure, strand
breakage and impairment of DNA function.
Synthesis:
N
N
HNO3/H2SO4
Ethylene chlorhydrin
N
Nitration
N
2-methyl
imidazole
CH3
O2N
N
N
H
O2N
CH3
2-methyl5-nitro
imidazole
CH3
CH2CH2OH
Metronidazole
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Uses: Treatment of specific protozoal infections like amoebiasis,
Trichomoniasis, Giardiasis, Balantidiasis.
Adverse effects: Diarrhea, Nausea, Insomnia, Ataxia, Vomiting
Metabolism: It is metabolized by cytochrome P450 system. Methyl
group is oxidized to hydroxy methyl group, ethanol side chain is
oxidized to an acid group (-CH2COOH) both are active metabolites.
Brand name: ALDEZOLE, METROGYL
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Triazole:
1
5
NH
N2
4
N
3
Triazole is a 5-membered heterocyclic ring containing three nitrogen
atoms.
e.g. Ribavirin, Triazolam, Alprazolam, Trazodone, Itraconazole,
Fluconazole, Terconazole .
Ribavirin
Antiviral
Triazolam
CNS depressant
Alprazolam
CNS depresasnt13
Fluconazole:
MOA: It inhibits cytochrome p450 dependent enzymes resulting in impairment of
ergosterol synthesis in fungal cell membrane of the fungi. It act by inhibiting
“Lanosterol – 14- α –demethylase” which is the enzyme involved in early stages of
synthesis of ergosterol. Inhibits oxidative demethylation and retains excess of
Lanosterol which destablishes the cell.
Squalene
Squalene
epoxidase
Squalene epoxide
Squalene epoxide
cyclase
HO
Lanosterol
Lanosterol 14alpha
demethylase
HO
HO
Ergosterol
14-demethylanosterol
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Uses : Treatment of Candidiasis and to control esophageal or
oropharyngeal Candidiasis, Vaginal Candidiasis. It is also used to treat
Cryptoccocal meningitis and Cryptococcosis in AIDS.
Adverse effects: Abdominal pain, Hepatotoxicity, Flatulence, Nausea
and vomiting, Diarrhea.
Metabolism: Glucuronide conjugation
Brand name: ADCON, ALFUCOZ
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Synthesis:
O
H2
C
Cl
F
O
H2
C
C
C
F
1,2,4-Triazole
EtOAc
Cl-CH2-CH2-C-Cl
F
F
F
O
N
N
N
H2C
H2C
N
C
H2C
C
N
N
O
F
C
H2
+
N
N
N
F
H
N
N
OH
N
C
N
N
Fluconazole
N
Trimethyl
sulfoxonium iodode
F
F
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Azole antifungals:
Higher dose
Fungicidal
Low dose
Fungistatic
Mechanism of action:
they are responsible for
leakage of essential cellular
component due to rupture/
lysis of cell membrane.
action is due to inhibition of
various enzymes involved
in biochemical processes.
They act by decreasing the CYP 450
membrane bound i.e. “Lanosterol – 14- α –demethylase” which is the
enzyme involved in early stages of synthesis of ergosterol.
Inhibits oxidative demethylation and retains excess of
Lanosterol which destablishes the cell.
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• Clotrimazole and Miconazole- substituted imidazoles
They are initially discovered and thus serve as lead molecules.
Drawback : 1) They are Hepatotoxic 2) Endocrine toxic
• Isosteric replacement of imidazole with “1,2,4-Triazole” led to
discovery of compound like Fluconazole, Itraconazole, which pocess
less side effects.
SAR of Azole antifungals:
• They are characterized by presence of a weekly basic imidazole /
1,2,4-triazole nucleus for antifungal activity.
• The amidine ‘N’ atom at 3rd position of imidazole and 4th position of
triazole are responsible for decreased concentration of heme iron due
to complexation
decrease Fe+2
decrease cell
respiration
Hypoxia
• All azole consists of 2 or 3 bulkier substituents like phenyl/substituted
phenyl group which imparts lipophilicity so as to disturb cell
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membrane.
• Presence of non polar groups increases lipid solubility while polar
groups increases aqueous solubility.
e.g. Fluconazole consists of 2 triazole nuclei which is highly water
soluble and can be administered by I.V route.
Clotrimazole:
Butoconazole:
Econazole :
N
N
Cl
CH2
CH2
CH2
C
S
H
Cl
Cl
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Sulconazole:
Miconazole:
Oxiconazole:
Tioconazole:
Ketoconazole:
Itraconazole:
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THIAZOLE : Thiazole is a 5 membered heterocycle containing sulphur
N
and nitrogen at 1,3 positions respectively.
Examples of drugs: cefpodoxime proxetil, ceftizoxime,
S
cefixime, cefotaxime, ceftriaxone, ceftazidim, cefpirome, cefipime,
ceftibuten, aztreonam, tigemonam, bacitracin A, ritonavir,
famotidine, nizatidine, thiamine, siomycin, thiosterepton, micrococin,
phleonycin, bleomycin, levamisole, sulfasomizole.
Aztreonam
Bleomycin ( antibiotic)
(monobactum)
Ritonavir (antiviral)
Levamisole(anthelmentic)
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Nizatidine
Treat peptic ulcer
Thiabendazole
anthelmentic
FAMOTIDINE:
MOA: It acts as a competitive reversible H2 antagonist
USES: Used for duodenal ulcer, gastric ulcer.
ADVERSE EFFECTS: GI discomfort, constipation, head ache, digginess
METABOLISM: Deamination, Glucuronide conjugation.
BRAND NAME: FALTIDIN, FAMOCID
SYNTHESIS:
COOC2H5
+
NH2CSNH2
N
Br-CH2COCOOC2H5
Thiourea
S
H2N
1.Ac2O
N
C
CH2
2.Li(C2H5)3H
CH2S
CN
CH2
N
CH2OH
N
HS-CH2-CH2
O
O
S
H3C
S
CHN
H3C
CHN
CH3OH/HCl
NH
N
N
H2C
S
H2N
S
C-OCH3
S
CH2
S
CH2
CH2
H2C
CH3S-C-NH2
HN
H2N
CH2
C
C-OCH3
NH
NH
NH
30-350C
NH2SO2NH2/CH3OH
Famotidine
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Thiadiazole:
5
S1
N2
4
N
3
It is a 5-membered heterocyclic ring containing 3 hetero atoms (one
sulphur and two nitrogen atoms).
e.g. Sulphamethizole, Cefazoline sodium, Timolol, Acetazolamide,
Methazolamide.
Sulfamethizole
Antibacterial
cefazoline sodium
antibiotic(antibacterial)
Acetazolamide
diuretic
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methazolamide (diuretic)
TIMOLOL IP:
MOA: Timolol is a Beta – blocker
Beta adrenergic receptors activate adenyl cyclase through G protein
which leads to accumulation of cyclic-AMP dependent protein kinase
which will phosphorylate the cellular proteins and produce
hypertension. The beta blockers bind to receptors and block their
activity and reduce hypertension.
USES: Antihypertensive agent.
ADVERSE EFFECTS: Fatigue, skin rash, alopecia, dry mouth, blurred
vision, heart failure.
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BRAND NAME: GLUCOMOL,IOTIM
METABOLISM: N- dealkylation, Glucuronide conjugation.
SYNTHESIS:
O
Cl
OH
Cl
O
ClCH2CH
N
CH2
CH3
Epichlorhydrin
N
OCH2CH
N
N
S
S
4-Chloro-3-hydroxy thiazole
H3C
Cl
OH
H3C
CH
H3C
CHNH2CH2CH(OH)CH2NH
N
H3C
N
S
O
OCH2CH(OH)CH2NHC
NH
O
CH3
CH3
CH3
N
N
N
S
Timolol
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Oxazole and Isoxazole:
Oxazole is a five membered heterocycle containing oxygen and nitrogen
at first and third positions respectively.
N
Isoxazole is a five membered heterocycle containing oxygen and
O
nitrogen at 1, 2 positions respectively.
N
O
Oxazole: Pimprinine, calcinomycin, griseoviridin, sulfamoxol, sulfaguanol
Isoxazole : Sulphamethoxazole USP, Sulfisoxazole USP, isocarboxazid, oxacillin,
cloxacillin, dicloxacillin, methicillin.
.
Sulfisoxazole (antibacterial)
Isocarboxazid(CNS stimulant)
cloxacillin (antibiotic)
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antibiotic
Dicloxacillin
(antibiotic)
Acivicin(antibiotic)
Sulphamethoxazole USP :
MOA:
NH2
PTERIDINE
PABA
NH2
Dihydopteroate synthetase
SULPHONAMIDES
COOH
P-Amino benzoic
acid
SO2NH2
Dihydropteroic acid
Sulphonamide
Folic acid
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USES: 1. It is used as a antibacterial agent.
2. Cotrimoxazole contains Sulphamethoxazole and trimethoprim
in 5:1 proportions to produce bactericidal and bacteriostatic action
against wide range of gram positive and gram negative organisms. It
is also used to treat respiratory and gastrointestinal tract infections.
Adverse effects: Diarrhoea, nausea, vomiting, renal failure.
Metabolism: Deamination, Glucuronide conjugation.
Brand name: ANTRIMA, BACTRIM.
Synthesis:
NHCOCH
NHCOCH
3
3
O
N
NH2
+
Condensation
H3C
SO2Cl
SO2NH
NH2
N
O
CH3
Alkaline hydrolysis
SO2NH
N
O
CH3
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Sulfamoxol:
CH3
N
H2N
SO2NH
O
CH3
USES: Antibacterial agent.
ADVERSE EFFECTS: Hypersensitivity skin reactions, crystalluria,
METABOLISM: Deamination, Glucuronide conjugation.
BRAND NAME: SULFUNO
O
SYNTHESIS:
O
H3C
ClSO3H H3C
-H2O
C NH
C NH
SO2Cl
4-Acetamido benzene sulfonylchloride
Acetanilide
CH3
N
H2N
NaOH
-HCl
O
O
H3C
C NH
SO2NH
CH3
CH3
N
O
CH3
CH3
N
H2N
SO2NH
Sulfamoxol
O
CH3
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Tetrazole: Tetrazole is a five membered heterocyclic ring containing
four nitrogen atoms.
N
N
N
N
H
Examples of drugs: Cefonacid sodium USP, ceforanide USP,
cefoperazone, cefmetazole, cefotetan, pentylenetetrazol.
Cefonacid
(antibacterial antibiotic)
Cefoperazone (antibacterial antibiotic)
ceforanide (antibacterial antibiotic)
cefmetazole
(antibacterial antibiotic)
pentylenetetrazol
CNS stimulant
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CEFOTETAN:
H2NOC
S
C
NaOOC
C
CH COHN
OCH3
S
S
CH3
N
O
N
C S
H2
COONa
N
N N
Cefotetan disodium
MOA: It act by inhibiting the synthesis of bacterial cell wall, resulting in
cell lysis. Beta lactum antibiotics are structurally similar to D-alanyl-Dalanines(component of peptidoglycon) , they are able to react with
penicillin binding proteins. Cephalosporins disrupt the synthesis of
peptidoglycon layers of bacterial cell wall.
USES: Antibacterial antibiotic.
ADVERSE EFFECTS: Nausea, vomiting, hypersensitivity reactions,
irritation etc.
METABOLISM: N-dealkylation, Desulphuration
BRAND NAME: CEFOTAN
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O
O
SYNTHESIS:
CS2
H2
C
C
NaOH
COOCH3
COOCH3
NaH
HN
NH2
S
Methyl malonate
monoamide
SNa
Br
COO-Na+
ONa
OCH3
HN-OCH2C
S
HCl
+
N
PH
N
S
SNa
O
CH2OAc
4-Carboxy-3-hydroxy
5-mercapto-isothiazole
sodium salt
COOH
7 Beta-bromoacetamido7alpha-methoxy cephalosporinic
acid
CH3
HO
COOH
N
HS
N
H
N
S
HN-OCH2CS
N
N
NaHCO3
OCH3
S
N
O
CH2OAc
COOH
H2NOC
S
C
NaOOC
C
CH
COHN
OCH3
S
S
CH3
N
N
O
C S
H2
COONa
Cefotetan disodium
N
N
N
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PYRAZOLE: It is a five membered heterocycle containing 2 nitrogen
atoms at 1, 2 position.
N
N
H
Examples of drugs: Muzolimine, Orisul, antipyrine, phenylbutazone,
oxyphenbutazone, sulfinpyrazone, pyrazofurin,
tetrazin, metamizole.
O
C6H5
N
C
N
C
H
(CH2)3CH3
O
Phenyl butazone
Antipyrine
NSAID
Orisul
Bacteriostatic
N
C6H5
HO
N
O
N
C H
N
C
O
NSAID
NO2
H3C
OH
(CH2)3CH3
Oxyphenbutazone
pyrazofurin
NO2
butazolidine( NSAID)
Phenylbutazone:
O
C6H5
N
C
N
C
H
(CH2)3CH3
O
Phenyl butazone
MOA:
Damaged tissue
PHOSPHOLIPID
phospholipase A2
ARACHIDONIC ACID
Cyclooxygenase
or
prostaglandin synthetase
NSAIDS
PROSTAGLANDINS
Uses: Non-steroidal anti-inflammatory agent .
Adverse effects: head ache, digginess, insomnia
Metabolism: N-Dealkylation, Aromatic hydroxylation
Synthesis:
O
C6H5
COOC2H5
C H
N
C
+
CH3 (CH2)3HH2C
COOC2H5
Diethyl-n-butyl
malonate
N
HN
HN
(CH2)3CH3
O
Phenyl butazone
Hydrazobenzene
37
PYRROLE: It is a five membered heterocyclic compound containing one
nitrogen atom.
N
H
Examples of Drugs : Tolmetin, Zomepirac etc..
H3C
C
N
H
CH2COOH
O
Tolmetin
NSAID
Chlorophyll
Heamoglobin
(blood)
(pigment)
Cyanacobalamine (vitamine)
FUSED RING SYSTEMS INVOLVING PYRROLE :
INDOLE:
vv
Tryptophan
Ergotamine
amino acid
antioxytocic
Reserpine
antihypertensive
Vinblastin(anticancer)
pindolol
(beta-bloker)
PYRROLIDINE
Nicotine
(withdrawal sympoms of tobacco smokers)
Phensuximide(CNSdepressant)
Procyclidine
remoxipride
antihistaminic
CNS depressant
Ethosuximide(CNS depressant)
methsuximide (CNS depressant)
TOLMETIN:
H3C
C
N
H
CH2COOH
O
Tolmetin
USES: Non-steroidal anti-inflammatory agent.
ADVERSE EFFECTS: Insomnia, blurred vision, head ache, digginess
METABOLISM: Metabolized to dicarboxylic acid (oxidation at benzylic
carbon atoms)
BRAND NAME: TOLECTIN
SYNTHESIS:
O
+
N
H
H3C
CH2CN
C
AlCl3
Cl
4-Methyl benzoyl
chloride
1-Methyl-2-cyanomethyl
pyrrole
H3C
H3C
NaOH
C
N
H
CH2CN
N
H
C
CH2COOH
O
O
Tolmetin
metabolised
HOOC
C
O
N
CH2COOH
CH3
Dicarboxylic acid metabolite
41
BARBITURATES
BARBITURATES
Barbiturates are central nervous system depressants. They
produce wide spectrum of CNS depression, from mild
sedation to coma, and have been used as a sedatives,
hypnotics, anesthetics and anticonvulsants.
Barbiturate development :
In 1864 von Baeyer synthesized the first barbiturate, barbituric
acid. The first hypnotic barbiturate, diethylbarbituric acid, was
synthesized by Fischer and Mering in 1903. In 1932 Weese and
Schapff synthesized the first rapid onset, short duration
barbiturate, methylated oxybarbiturate hexobarbital. Thiopental
was first administered by Waters and Lundy in 1934.
CLASSIFICATION
Chemistry of barbiturates:
1.
Barbiturates are derivatives of barbituric acid which is devoid of sedative and
O
OH
hypnotic activities.
HN
N
O
HO
HN
N
O
OH
keto-enol tautomerism of barbituric acid
2.
Barbituric acid is described as “ cyclic ureide of malonic acid”. Barbituric acid can
be made by condensing urea with ethyl malonate in presence of sodium
ethoxide
O
NH2
O
H5C2O
HN
H2N
O
Urea
C2H5ONa
C2H5O
O
HN
O
Ethylmalonate
2.
O
Barbituric acid
Clinically important hypnotic-sedative barbiturates have substitutions at
Sites 1,2 and especially 5 of barbituric acid.
Mechanism of Action
Barbiturates potentiate the effect of GABA at the GABA-A receptor. The
GABA-A receptor is a ligand gated ion channel membrane receptor that
allows for the flow of Cl through the membrane in neurons. GABA is the
principle neurotransmitter for this receptor which upon binding causes the
channel to open and creates a negative change in the transmembrane
potential. This makes it an Inhibitory neurotransmitter
GABA binding site
Barbiturate binding site
GABA
Barbiturates potentiate the effect of GABA by binding to the GABA-A receptor at a
nearby site and increasing the chloride flow through the channel. Barbiturates
also block the AMPA receptor which is sensitive to glutamate, the excitatory
neurotransmitter. Glutamate performs the opposite effect from GABA restricting
ion flow and increasing the transmembrane action potential of the neuron. By
blocking this action Barbiturates serve to increase the duration of the receptor
response to GABA and extend the depressed condition of the cell.
USES:
• Barbiturates have been used to treat insomnia but they should not be
used regularly bcoz they are not effective for longer than 2 weeks.
• They are used to relieve nervousness or restlessness during day time.
If too much of barbiturate is used it may become habit-forming.
• They may be used before surgery to relieve anxiety or tension.
• Some of them are used as anticonvulsants to control seizures
(epilepsy).
• However they are generally been replaced by safer medicines for the
treatment of insomnia, day time nervousness or tension.
• They are used as sedative hypnotic drug, anesthetics.
SAR:
1) Hypnotic activity: side chains at position-5 (especially if one of them
is branched ) is essential for activity.
2) Potency and duration of action: length of side chain at position-5
influences potency and duration of action. Ex: Secobarbital and
Thiamylal are slightly more potent than pentobarbital and thiopental
respectively.
3) More rapid onset and short duration of action: sulphur instead of
oxygen at position-2. Ex: Thiamylal and Thiopental have more rapid
onset and shorter duration of action than Secobarbital and
Pentobarbital respectively.
4) Increased incidence of excitatory side effects: methylation at
position -1 (Methohexital).
5) Increased potency, rate of onset : increase in lipophilicity of the
compound .
6) Introduction of polar groups into C-5-alkyl side chain makes the
compound more hydrophilic in nature (excreted).
7) Branched , cyclic, unsaturated side chain at C-5 position generally
reduce the duration of action due to increased ease of metabolic
conversion to a more polar inactive metabolite.
8) stereoisomerism: though their l-isomers are nearly as potent as their
d-isomers, barbiturates are marketed as racemic mixtures.
Side effects: hangover with drowsiness, digginess, ataxia, respiratory
depression. Hypersensitivity reactions, headache,
confusion , slurred speech, slowed reflexes.
Metabolism: N-dealkylation, Desulphuration
Chemical structure of the barbiturates
(Seconal)
(Pentothal)
(Amytal)
(Nembutal)
(Mebaral)
• Phenobarbitone: It occurs as sodium salt. it is hygroscopic, water
soluble, bitter taste, odorless, white crystalline power.
Synthesis:
O
O
O
1.
O
O
C6H5
Na
O
CH
C
O
Ethylphenylacetate
C
C
OC2H5
OC2H5
O
diethyloxalate
O
Ethyloxalophenylacetate
O
O
2.
C6H5
CH
C
C
C
OC2H5
C6H5
-CO
OC2H5
CH
C
OC2H5
OC2H5
O
O
C
O
Ethyloxalophenylacetate
C2H5ONa C2H5Br
O
OC2H5
OC2H5
3.
O
O
O
OC2H5
OC2H5
HN
urea
C2H5
O
C6H5
O
HN
O
Phenobarbitone
Amobarbitone
H3C
O
O
OC2H5
OC2H5
H3C-HC-HC-H2C
NH2
HN
H2N
C2H5
O
O
CH3
CH2CH2CHCH3
HN
O
O
Amobarbitone
Mephobarbital
O
H3C
OC2H5
OC2H5
C6H5
NH2
H2N
O
N
C2H5
O
O
O
C6H5
HN
O
Mephobarbital
• REFERANCES :
• TEXT BOOK OF ORGANIC MEDICINAL &
PHARMACEUTICAL CHEMISTRY- WILSON & GISVOLD
• FOYE’S PRINIPLES OF MEDICINAL CHEMISTRY FIFTH
EDITION
• MEDICINAL CHEMISTRY- NADENDLA RAMA RAO
• TEXT BOOK OF MEDICINAL CHEMISTRY- S.PANDEY
• A TEXT BOOK OF MEDICINAL CHEMISTRY- KADAM
• BIOPHARMACEUTICS AND PHARMACOKINETICS
D.M BRAHMANKAR SUNIL B. JAISWAL